Anti-cancer compounds that are already known or commercially marketed exert their anti-cancer properties through various ways, including through direct action on cancer cells. A number of the anti-cancer agents that act directly on cancer cells block cancer cell proliferation or are cytotoxic for cancer cells.
However, even after complete removal or treatment of a primary cancer, a malignant tumour often metastasizes. A metastatic malignant tumour is formed at a location distant from the primary lesion as a result of the metastasis of the primary tumor. This is one of the most important concerns in cancer therapy. Specifically, even if a primary lesion is treated, a patient may die because of the growth of a tumor that has metastasized to another organ. In the case of many types of clinically diagnosed solid cancer (a type of tumor that is a primary lesion resulting from the local growth of cancer), surgical obliteration is thought to be the first means for treatment. However, primary cancer cell metastasis is often observed after surgical operation. Cancer infiltration at a metastatic site spreads over the whole body, so that the patient will die due to the growth of metastatic cancer. It has been reported that for individual bodies having resectable tumors, primary tumor growth or local recurrence are often causes of death. It is thus currently considered that almost 40% of cancer victims with operable tumors will finally die because of metastatic disease following surgical operation.
Accordingly, malignant tumor metastasis is the most common reason for failed cancer therapies (see Bertino et al., (edited in 1996), Encyclopedia of Cancer, Academic Press; Devita et al., (edited in 1997), Cancer: Principles & Practice of Oncology, Lippincott, Williams and Wilkins; Cavalli et al., (1996), Textbook of Medical Oncology, Dunitz Martin Ltd; Peckham et al., (edited in 1995), Oxford Textbook of Oncology, Oxford Univ. Press; and Mendelsohn et al., (1995), The Molecular Basis of Cancer, Saunders, Philadelphia).
Malignant melanoma, breast cancer, lung cancer, colon cancer, and prostate cancer are thought to be cancer types that tend to metastasize. The range of metastasis differs depending on a cancer type. The lungs and the liver are well known as target organs of cancer, and the brain or the bone marrow is also a target organ at a high frequency. Bone metastasis differs from metastasis to other organs, such that it rarely directly threatens life. However, bone metastasis is complicated by excruciating bone ache, the restriction of physical activity, or the like, thereby significantly lowering patient quality of life (QOL) and indirectly causing one's early death.
Metastasis is a very complex process resulting of various genetic or epigenetic mutations and each stage of metastasis is believed to be regulated by specific intracellular signal transduction pathways. Invasion mechanisms initiate the metastatic process and consist of changes in tumour cells adherence to cells and to the extracellular matrix, proteolytic degradation of surrounding tissue and motility to physically proper a tumor cell through tissue, all those steps are specifically regulated by signal transduction pathways.
The multi-step process of metastasis includes, (i) release of malignant cells from the primary neoplasm, (ii) migration of cancer cells into circulation, (iii) adhesion at distant sites, and (iv) growth of the disseminated cancer cells within the vessels or within the tissue following extravasation. Each step in this process requires different types of interaction between cancer cells and the host microenvironment.
While the details of the mechanisms by which metastasis occurs and thus may be inhibited have not been fully elucidated yet, it is however obvious that the biological mechanisms involved in the transformation of a non-cancer cell to a cancer cell are clearly distinct from the mechanisms involved in the generation of cancer cell metastasis (Steeg P S, Nat. Medicine 2006, vol. 12, (8), 895-904). For example recent works establish a clear distinction between several cellular pathways leading to cancer cell proliferation and metastatic invasion mechanisms (McLean, G. et al., Nat. Rev. Cancer 5, 505-514 (2005); Playford, M. & Schaller, M., Oncogene 23, 7928-7946 (2004); Birchmeier, C et al., Nat. Rev. Mol. Cell. Biol. 4, 915-925 (2003)).
Moreover, while identification of specific metastasis genes is difficult because of the need for several complementary functions that might be fulfilled by different genes in different contexts, more than 20 metastasis suppressors have currently been identified. Metastasis suppressors act by different mechanisms than tumor suppressors, and have no effect on primary tumors. These genes inhibit metastases without blocking tumour formation (Rinker-Schaeffer C W et al., Clin Cancer Res 2006; 12:3882-89; Berger J C et al., Cancer Biol Ther 2005; 4:805-12; Nash K T et al., Front Biosci 2006; 11:647-59; Shevde L A et al., Cancer Lett 2003; 198:1-20; Steeg P S et al., Clin Breast Cancer 2003; 4:51-62).
It has therefore became obvious that if the targeting of the proliferation and/or apoptosis mechanisms may be needed in order to eliminate the primary tumour, it is necessary, in order to achieve a complete remission, to differentially address metastatic processes.
Indeed, although anti-cancer agents, including those having anti-proliferative activity against cancer cells, have proved therapeutic efficiency against primary tumors, almost none of these anti-cancer agents possess concomitantly anti-metastasis activity.
Preclinical studies indeed report differential effects of drugs on primary and metastatic disease. These data illustrate that compounds validated on the reduction of the size of primary tumor may not work on metastatic disease. On the contrary, anti-metastatic efficacy may not be validated in tests based on the reduction of primary tumor size (Steeg P S, Nature Medicine, 12 (8), 895-905 (2006); Lang, J. Y. et al. Clin. Cancer Res. 11, 3455-3464 (2005); Shannon, K. E. et al. Clin. Exp. Metastasis 21, 129-138 (2004); Manni, A. et al. Clin. Exp. Metastasis 20, 321-325 (2003); Cairns, R. A. & Hill, R. P. Cancer Res. 64, 2054-2061 (2004); Lovey, J. et al., Strahlenther. Onkol. 179, 812-818 (2003); Nasulewicz, A. et al. Biochim. Biophys. Acta 1739, 26-32 (2004)).
Furthermore, other studies have shown that chemotherapeutics targeting the primary tumor can alter metastatic properties. For example, in vitro treatment of nasal carcinoma cell line with melphalan has been shown to increase its invasiveness (Liang, Y. et al. Eur. J. Cancer 37, 1041-1052 (2001)). The mechanisms responsible for the effect on metastasis are unknown and may be multifactorial. There are at least the following two possibilities: (a) that the treatment is accelerating mutation and exerting a selective pressure that encourages the outgrowth of more aggressive cellular variants or (b) that the stress associated with the treatment is inducing epigenetic changes such as alterations in gene expression that enhance the ability of cells to form viable metastases (Cairns R. A. & Hill R. P. Cancer Res., 64, 2054-61 (2004)).
Therefore regarding the development of anti-metastatic drugs, the most interesting target are the molecules of the cellular processes which control the metastatic spread without interfering with the primary tumour growth.
In the last 20 years, some teams have dedicated themselves to find “true” (i.e.: specifically targeting metastatic processes) antimetastatic drugs. Some of those anti-metastatic drugs, such as razoxane, inhibit intravasation of metastatic cells by elaborating a physical barrier, which does not limit the growth of the primary tumour (Bergamo et al., Dalton trans., 2007, 13, 1267-1272). Most of them inhibit different steps of colonization (Perret & Crepin, Fundamental and Clinical Pharmacology, 2008, 22, 465-92).Previous works which have shown a direct relationship between the ability of cancer cells to migrate in vitro and their capacity to metastasize in vivo, have also opened possibilities to identify new anti-metastatic targets (see notably Giamperi et al., 2009, Nature Cell Biology, Vol. 11(11): 1287-1296; Patent Application no US 2003/0054985, Hazan et al., 2000, The Journal of Cell biology, Vol. 148(4): 779-790; Yang et al., 2009, Cancer Cell, Vol. 15: 124-134).
A compound that has been the subject matter of promising experimental testing, including preliminary clinical trial phases, is the alkylglycerophospholipid compound named edelfosine (ET-18-OCH3) (Vogler et al., Cancer Invest, 1998, 16(8):549-53, Candal et al., Cancer Chemother Pharmacol, 1994, 34(2), 175-8).
However, while edelfosine has been described in the art to possess anti-angiogenic and possibly anti-invasive effects, a clear understanding of his molecular action is lacking. For example it has been shown that edelfosine exerts a biphasic effect on angiogenesis depending on the dose (Vogler et al., Cancer Invest, 1998, 16(8):549-53, Candal et al., Cancer Chemother Pharmacol, 1994, 34(2), 175-8, Cajate C & Mollinedo F, Current Drug metabolism, 2002, 3, 491-525). Moreover, other closely related glycerolipids, such as PAF (Andrade S P et al., Int. J. Exp. Pathol., 1992, 73, 503-13) or butyryl-glycerol (Dobson D E, et al., Cell, 1990, 61, 223-30) have been reported to be pro-angiogenic.
Moreover, Edelfosine is not a “true” anti-metastatic drug, since it also targets the primary tumor growth and exerts pro-apoptotic effects (Gajate C and Mollinedo F, Curr. Drug Metab. 3, 491-525; Nieto-Miguel et al., 2007, Cancer Res, 67 (31); Estella-Hermoso de Mendoza et al., 2009, Clin Cancer Res, 15(3), 858-864).Lastly, edelfosine is well known to be highly toxic when it is administered to human and its clinical therapeutic use was notably hampered by major adverse side effects (Gajate C and Mollinedo F, Curr. Drug Metab. 3, 491-525).
There is thus still a need in the art for methods for inhibiting tumor metastasis, and in particular for methods which inhibit metastasis without causing serious side effects to the treated cancer patient.